The Role of the Autonomic Nervous System in Vasovagal Syncope

Abstract

The mechanism of vasovagal syncope (VVS) is multifacetedly intricate and involves a delicate balance within the autonomic nervous system (ANS). This review delves into the complex interplay between the ANS and VVS, elucidating the pivotal role that autonomic dysfunction plays in the pathophysiology of this condition. Through a comprehensive exploration of the sympathetic and parasympathetic branches of the ANS, this review will provide insights into the mechanisms that underlie VVS. Additionally, this chapter discusses established and emerging research on the management vasovagal syncope. With a focus on both the clinical and mechanistic aspects of VVS, this review article offers a valuable resource for readers seeking a deeper understanding of this enigmatic condition and its connection to the autonomic nervous system.

Introduction

Understanding of the autonomic regulation of the heart is essential in comprehending the development of many cardiovascular diseases.¹ The autonomic nervous system (ANS) plays an intricate role in the pathophysiology of vasovagal syncope (VVS).² Many of the known and emerging treatments for VVS, sinus node dysfunction and functional atrioventricular (AV) block involve the neuroaxial modulation of the cardiac ANS.^2,3 In this review, we will discuss the anatomic aspects of the cardiac ANS. We will also outline the normal and abnormal responses of the ANS as it relates to VVS. Lastly, we will discuss the established treatments for VVS and explore the emerging research regarding ANS modulation in the treatment of VVS.

The Autonomic Nervous System

The ANS is the branch of the nervous system that controls and regulates visceral functions without conscious effort.⁴ It regulates heart rate, blood pressure, body temperature, respiratory rate as well as other bodily functions to maintain homeostasis.⁴ The ANS is a major regulator of the cardiovascular system and imbalances in its function can lead to VVS .^1,5

The Anatomy and Function of the Cardiac Autonomic Nervous System

The two interacting arms of the ANS that regulate the heart are the sympathetic nervous system and parasympathetic nervous system.⁴ Although they are simplistically thought of as antagonistic in effects, their interaction is complex and often non-algebraic.⁶ The location and connections of their neurons also differ (Figure 1).

Figure 1:

Anatomy of the Cardiovascular Autonomic Nervous System

ANS autonomic nervous system

Cardiac sympathetic efferent fibers originate from the sympathetic autonomic ganglia along the cervical and thoracic spinal cord (superior cervical ganglia, stellate ganglia and thoracic ganglia).^1,2,7 These ganglia house post-ganglionic neurons which then travel from the spinal cord to the surface of heart.^2,7 In contrast, cardiac parasympathetic efferent fibers originate from the medulla oblongata (in the brainstem), with the preganglionic fibers carried almost entirely within the vagus nerve which then converge in distinct peri-cardiac fat pads that contain the parasympathetic ganglia.^1,2,7 This difference in origin and location of the sympathetic and parasympathetic ganglia and their corresponding efferent fibers play an integral role in the effects of endocardial radiofrequency ablation for cardiac arrhythmias and vasovagal syncope,³ as will be further discussed later.

The heart is also innervated exquisitely by a complex intrinsic cardiac ANS that has been referred to as the “little brain of the heart.” ^7,8 Numerous cardiac ganglia are found within the heart, each of which contain thousands of neurons that form synapses with the sympathetic and parasympathetic fibers that enter the pericardium.^5,7,8 Many of these cardiac ganglia organize into ganglionated plexi (GP) within the epicardial fat pads along the atria and the ventricles.³ These GPs function as integration centres that modulate the interaction between different branches of the cardiac ANS and consequently impact the sinus rate, atrioventricular conduction and the electrophysiological properties of the heart.^1,7,8 In addition, they also participate in the local reflex responses within the heart.⁹

Cardiac ganglia contain different anatomical subtypes, including the two major phenotypes of neurons: adrenergic and cholinergic neurons.^1,7 In the heart, sympathetic post-ganglionic neurons release norepinephrine (NE) and are therefore adrenergic.⁴ Meanwhile, parasympathetic neurons release acetylcholine in their synapses and are thus cholinergic.⁴

Adrenergic receptors (α1, α2, β1, and β2) are expressed in the heart and vascular smooth muscle. In the heart, binding of NE to these receptors promotes inotropy (increased contractility), chronotropy (increased heart rate) and dromotropy (enhanced atrioventricular (AV) nodal conduction).^4,7 In the blood vessels, activation of α receptors promote vasoconstriction while β2 adrenergic receptors promote vasodilation.⁴ In contrast, cholinergic (muscarinic) receptors in the heart slow heart rate (HR) and conduction velocity in the nodal and atrial tissue. (Figure 1).⁴

The Baroreceptor Reflex and Normal Blood Pressure Regulation

The autonomic control of the heart is regulated by several reflex arcs between sensory afferents throughout the body and efferent pathways from the central nervous system.⁷ The baroreceptor reflex arc plays an integral role in maintaining normal blood pressure (BP) (Figure 2).⁵

Figure 2:

Baroreceptor reflex during increased blood pressure

BP blood pressure, CVLM caudal ventrolateral medulla, DMNV dorsal motor nucleus of the vagus, HR heart rate, NTS nucleus tractus solitarius, RVLM rostral ventrolateral medulla, SVR systemic vascular resistance

BP is monitored continually by receptors in the carotid arteries, aorta, lungs, coronary arteries and splanchnic circulation in the gut.¹⁰ These receptors are called baroreceptors and consist of mechanosensory neurons in large arteries that are activated when arterial walls are stretched to due increased BP.¹⁰

A rise in blood pressure stretches the arterial wall, resulting in increased firing of baroreceptors.¹⁰ Baroreceptor afferent neurons travel vial the glossopharyngeal and vagus nerves to synapse in the nucleus tractus solitarius (NTS) in the medulla.^5,6,10 The NTS sends signals to activate parasympathetic neurons in the dorsal motor nucleus of the vagus (DMNV) and the nucleus ambiguous.^7,10 Signals are then sent down the vagus nerve to cause acetylcholine release in the heart, leading to decreased heart rate (HR) from increased vagal tone.¹⁰ In addition, the NTS also projects to the caudal ventrolateral medulla (CVLM)¹⁰. In the presence of increased BP, the CVLM inhibit preganglionic sympathetic neurons in the rostral ventrolateral medulla (RVLM), which then reduce efferent sympathetic tone¹⁰. This leads to decreased HR, cardiac contractility and systemic vascular resistance (SVR) (Figure 2).

In contrast, a drop in BP results in decreased arterial stretch and reduced baroreceptor firing rate. The baroreflex response to decreased blood pressure is well-demonstrated during standing up. When blood pools down the veins, blood flowing back to the heart (venous return) decreases, causing the cardiac output and arterial BP to fall.⁵ This results in decreased baroreceptor efferent signals to the medulla, leading to increased sympathetic outflow (resulting in increased HR, contractility and SVR) and decreased parasympathetic outflow (causing an increase in HR) (Figure 3).¹⁰

Figure 3:

Baroreceptor reflex during decreased blood pressure (e.g. after standing up)

BP blood pressure, CVLM caudal ventrolateral medulla, DMNV dorsal motor nucleus of the vagus, HR heart rate, NTS nucleus tractus solitarius, RVLM rostral ventrolateral medulla, SVR systemic vascular resistance

In summary, during a decrease in BP (such as during an active stand test), baroreceptor firing decreases and BP is maintained via increased HR (via increased sympathetic and decreased parasympathetic output), contractility and SVR (predominantly due to increased sympathetic output).

The Vasovagal Reflex and Blood Pressure Regulation in Vasovagal Syncope

As the most common cause of syncope, VVS is one type of reflex (or neurocardiogenic) syncope.¹¹ Reflex syncope is a transient loss of consciousness caused by reflex bradycardia and/or vasodilation due to a specific trigger.¹¹ In VVS, this trigger often involves prolonged standing or sitting, pain or stress. ^11,12 Regardless of the trigger of VVS, these basic elements of the vasovagal response are postulated to occur: the medulla is activated indirectly or directly, leading to increased activity of the parasympathetic nervous system and decreased activity of the sympathetic nervous system.¹¹ The response can be classified on head-up tilt-testing (HUTT) according to the modified Vasovagal Syncope International Study (VASIS) criteria: Type 1 - mixed response: mixed BP and HR fall without severe bradycardia; Type IIa - cardioinhibitory without asystole: severe bradycardia (HR <40 bpm) for >10 seconds without asystole; Type IIb - cardioinhibitory with asystole: asystole occurs for >3 seconds with HR decrease coinciding or preceding BP fall; and Type III - vasodepressor: BP fall with minimal decrease in HR¹².

In VVS, normal baroreceptor control is lost or overridden.^5,11 The ANS reflex pathways in VVS differ from normal baroreceptor-driven BP control in at least 2 ways. First, the reflex response to decreased blood pressure in VVS lead to arterial hypotension. Second, BP and HR decrease together, most particularly in the final stages of VVS.⁵

In cases of patients with orthostatic VVS during HUTT, Van Dijk et al. showed that the slow decrease in stroke volume from venous pooling was initially accompanied by an appropriate and corrective increase in HR with incomplete success, as the BP continued to fall. Moreover, in 91% of cases, inappropriate cardioinhibition occured towards the end of the reflex, with consequent bradycardia, causing further acceleration of BP drop, which led to syncope.⁵

The neural mechanism of VVS remains elusive and controversial in some areas. The most widely cited mechanism has been explained by the Sharpey-Shafer model,¹³ also known as the “Ventricular Hypothesis”, and is postulated as follows (Figure 4): An initiating event, such as prolonged standing, causes venous pooling leading to reduced venous return to the heart with consequent decreased stroke volume and BP. This leads to decreased baroreceptor efferent signals to the NTS in the medulla, as that normally seen in the baroreceptor reflex arc. This causes appropriate sympathetic activation and parasympathetic suppression, leading to increased chronotropy and inotropy. However, in VVS patients, it is postulated that this vigorous contraction of an underfilled ventricle stimulates ventricular mechanoreceptors which send afferent signals through unmyelinated nerve fibers (“C fibers”) to NTS. The NTS then sends efferent signals thought to override or counteract the baroreceptor reflex by causing withdrawal of sympathetic tone and increase in parasympathetic output, causing paradoxical vasodilation and bradycardia, leading to further hypotension and loss of consciousness.⁵

Figure 4:

The autonomic nervous system response during vasovagal syncope

BP blood pressure, CVLM caudal ventrolateral medulla, DMNV dorsal motor nucleus of the vagus, HR heart rate, NTS nucleus tractus solitarius, RVLM rostral ventrolateral medulla, SVR systemic vascular resistance

Autonomic Modulation for the Treatment of Vasovagal Syncope

All treatment approaches to VVS can be related back to the ANS, with treatment mechanisms involved in either preventing or counteracting the vasovagal reflex (Figure 5).¹⁴

Figure 5:

Treatments targeting different aspects of the pathophysiology and autonomic nervous system response in vasovagal syncope. Figure adapted and modified with permission from: Ballantyne BA, Letourneau-Shesaf S, Raj SR. Management of vasovagal syncope. Auton Neurosci. 2021 Dec;236:102904. doi: 10.1016/j.autneu.2021.102904. Epub 2021 Nov 4. PMID: 34763249.

CPM counterpressure maneuvers, NET norepinephrine transport, SSRI selective serotonin receptor inhibitor

Societal guidelines have outlined in detail specific recommendations for the management of VVS.^15,16,17 We will broadly highlight specific treatments and show their role in the autonomic modulation of VVS (Figure 5).

Nonpharmacological Therapy for Vasovagal Syncope

Non-pharmacological therapy, which should be employed in all VVS patients, is the foundation of VVS treatment. Non-pharmacological interventions primarily focus on improving overall volume and preventing the reflex response caused by orthostatic stress or other triggers.

Education and Counselling

Education about the diagnosis, the physiological mechanisms and the typical prodromal symptoms of vasovagal syncope can be useful and reassuring for patients.¹⁸ This allows them to understand the benign nature of VVS and to take ownership in the prevention and management of their symptoms. In an observational study of 371 patients with 2 or more episodes of VVS referred to a syncope centre, Aydin et al showed that a standardized educational protocol about VVS mechanisms and prognosis, avoidance of triggers, and lifestyle modifications, significantly reduced traumatic syncope and syncope recurrence in clinic follow-up.¹⁹

Increased Salt and Water Intake

The cornerstone of VVS management is increased salt and water intake, which aims to increase intravascular blood volume, and consequently the cardiac venous return (Figure 5).^14,17

The rationale for liberal salt use in VVS is that the body’s sodium content determines plasma volume and that increase in plasma volume lead to increased orthostatic tolerance in VVS patients.²⁰ In a double blind randomized placebo trial involving patients with unexplained syncope who were randomly allocated to salt tablets and placebo, El-Sayed et al showed that salt supplementation significantly increased plasma and blood volumes, improved orthostatic tolerance and decreased baroreceptor sensitivity.²⁰ In children with vasodepressor VVS (VASIS Type III) randomized to oral rehydration salts plus education, Li et al showed that salt supplementation lead to significant reduction in syncope recurrence compared to children with VVS who were randomized to the education group only.²¹

In addition to salt intake, rapid and increased water ingestion also help prevent VVS recurrence. Previous studies have reported this as an effective way to prevent orthostatic intolerance. Jordan et al showed that acute ingestion of water can elicit a potent vasopressor response in patients with autonomic failure and in healthy controls. Acute ingestion of 480mL of water raised systolic blood pressure by 11mmHg thirty-five minutes after drinking. The authors also observed an increase in plasma norepinephrine concentration 30 minutes after water drinking, suggestive of sympathetic activation elicited by water ingestion.²²

In the absence of contraindications, VVS patients should be encouraged to increase their salt and fluid intake to at least 2 g/day of sodium and 2 to 3 L/day of water.^15,16,17,18

Physical Counterpressure Maneuvers

In younger patients who experience and recognize prodromal symptoms, physical counterpressure maneuvers may help prevent syncope.¹⁸ Physiologic studies have shown that isometric counterpressure maneuvers of the legs or arms (e.g. leg crossing and hand grips) are able to induce a significant blood pressure rise prior to the onset of syncope.²³–²⁵ This is postulated to be mediated by sympathetic nerve discharge and increased vascular resistance during maneuvers and by mechanical compression of the venous system in the legs and abdomen, leading to increased venous return.²³ The Physical Counter Pressure Maneuvers Trial (PC-Trial) is an RCT involving young (average 38.6 years old) patients with recurrent VVS and recognizable prodromal symptoms. It showed that patients who were randomly assigned to conventional therapy alone versus conventional therapy plus CPM training had significantly lower recurrence of syncope, with a significant 39% relative risk reduction.²⁵

Yoga

Yoga has been shown in several studies to favorably modulate the ANS by balancing the sympathetic and parasympathetic drives.²⁶ In addition, mindfulness and meditation, key components of yoga, have been shown to help reduce emotional stress, a potential trigger for VVS.²⁷ A recent small (n=55) RCT by Sharma et. al. studied the effectiveness of yoga as an adjuvant therapy in younger VVS patients (mean age 39 + 15 years old) with a positive HUTT and at least 2 episodes of syncope or presyncope.²⁸ All patients were offered guideline-based therapy, with the intervention arm also placed on a specialized yoga training program. This consisted of 8 supervised sessions in the first 2 weeks, 2 supervised sessions in the second month, followed by at least 5 unsupervised home daily sessions in a week for 12 months with regular phone follow-up and daily logs. Results showed that more patients in the yoga group remained free of events and had improved quality of life scores at 12-month follow-up, compared to patients who had standard therapy alone. Given the open label design of this study, and the more frequent and supervised follow-up that the yoga group experienced, it is difficult to know whether yoga itself versus other mechanisms led to the difference seen in the groups. It is possible that the yoga group had decreased event rates and better reported quality of life due to the different level of “expert touch” that they experienced during the study. Further larger and more methodologically robust studies are needed to help tease out whether yoga, or any other intervention resulting in a more intensive interaction or “expert touch” from healthcare providers, are enough to help improve VVS remission and the quality of life of VVS patients.²⁹

Pharmacological Therapy for Vasovagal Syncope

For VVS patients with recurrent episodes, intensification of non-pharmacologic treatment and consideration for pharmacological therapy is appropriate.¹⁴ Each of the pharmacological therapies also target or prevent the occurrence of the vasovagal neural response.

Midodrine

Midodrine is a prodrug that is converted to desgly-midodrine, an a1-adrenergic receptor agonist that causes vasoconstriction.³⁰ It opposes the vasodepressor effects seen in VVS. It causes both venous and arterial vasoconstriction leading to an increased BP and reduced venous pooling (Figure 5). This is thought to prevent the reduced cardiac output from decreased preload, which is an early feature of the vasovagal reflex.¹⁴

The largest prospective placebo-controlled randomized controlled trial (RCT) involving the use of midodrine in VVS patients is the Fourth Prevention of Syncope Trial (POST 4). In this multicentre RCT involving 133 young (median age of 32 years old), and otherwise healthy patients who had recurrent syncope (median of 6 episodes in the prior year), midodrine (dose range of 2.5mg twice daily to 10mg three times daily) was associated with a lower likelihood of syncope recurrence; with an absolute risk reduction of 19% and number needed to treat of 5.3 (CI 2.8-47.6).³⁰

A systematic review and meta-analysis by Liu et al. involving 7 RCTs comparing midodrine against placebo or non-pharmacological standard of care in patients with recurrent VVS showed moderate-to-high quality of evidence to suggest that midodrine reduces the likelihood of syncope during HUTT or in clinical settings.³¹

Midodrine is well-tolerated in most patients but comes with the risk of causing supine hypertension.²⁶ Caution should be used in older adults who have hypertension, heart failure, and urinary retention. In addition, midodrine is listed as a Food & Drug Administration (FDA) Pregnancy Class C medication (adverse fetal effects in animal studies; no well-controlled human studies). It should be prescribed in conjunction with appropriate contraception in females of childbearing potential.^14,30

Fludrocortisone

Fludrocortisone is a mineralocorticoid agonist. It increases real sodium absorption, thereby expanding plasma volume and preload. By plasma volume expansion, it is thought to increase venous return and consequently prevent the physiological cascade leading to the vasovagal reflex (Figure 5).^14,18

The Prevention of Syncope Trial 2 (POST 2) is a randomized, placebo-controlled, double-blind trial that assessed the effects of fludrocortisone (target of maximum dose of 0.2mg daily) against placebo in young patients (median age 30 years old) with highly symptomatic, recurrent vasovagal syncope (median of 15 syncopal spells over a median of 9 years). The trial did not meet its primary objective of demonstrating a pre-specified relative risk reduction of 40% in the fluodrocortisone arm. However, it did show that there was a trend towards lower 12-month syncope event rates in the fluodrocortisone arm, with a non-statistically significant relative risk reduction of 27% compared to placebo. Post-hoc analyses showed a significant benefit for fluodroocortisone after 2 weeks of dose stabilization at 0.2mg/day.³²

Guidelines include the use of fluodrocortisone as a reasonable pharmacotherapy for VVS, with a preference for younger patients and those with low-normal systolic BP.^15,16,17 Due to its effects on plasma volume and BP, it should be used in caution in patients with heart failure or refractory hypertension.¹⁴ The dose should ideally be pushed to 0.2 mg/day for optimal efficacy, and to wait for 2 weeks before starting to assess benefit. Like midodrine, it is also classified as an FDA Pregnancy Class C drug and should be avoided in pregnant women.¹⁴

Beta-adrenergic Blockers

Beta-adrenergic blockers have traditionally been used to treat VVS. When decreased venous return occur during the upright posture, excessively high heart rates have been postulated to limit stroke volume and cardiac output, and that beta-blockers may help prevent this.³³ In addition, it has been thought to help prevent the cascade of events initiated by the baroreceptor-triggered increase in sympathetic tone during VVS (Figure 5).¹⁴

Previous randomized trials and systematic reviews did not find any benefit in beta-blockers against VVS recurrence in unselected populations.^34,35 An observational study by Natale et al showed that the effect of B-blockers in preventing the vasovagal reflex may be age-dependent, with patients >42 years old having a lower likelihood of syncope on metoprolol.³⁶

A pooled meta-analysis of an observational study by Sheldon et al and the Prevention of Syncope Trial (POST) trial showed that there was a difference in the response to B-blockers between patients with recurrent VVS treated with B-blockers aged <42 years and >42 years, with lower likelihood of syncope recurrence in those >42 years old (hazard ratio of 0.52, CI 0.27-1.01).³⁷

Taken together, these studies suggest that B-blockers are relatively ineffective for VVS and should be avoided in younger patients. However, it may be considered as an addition to medical treatment of VVS in older populations, especially in those who are unable to tolerate midodrine or fludrocortisone due to comorbidities or to the drugs’ associated side effects. European and American guidelines diverge in their recommendations regarding beta-blockers, with ESC recommending against (Class III) their use, while ACC/AHA/HRS having a Class IIb recommendation for their use in patients ≥ 40 years old with recurrent VVS.^15,17

Selective Serotonin Reuptake Inhibitors

Several neurotransmitters are believed to facilitate vasovagal reactions by inhibiting the central adrenergic system.³⁸ One of these neurotransmitters is 5-hydroxy-triptamine (serotonin). Serotonin may play an important role in the CNS’ modulation of the BP and HR. In experimental models, it was found that injection of serotonin into intracerebral areas produced a similar sympathetic withdrawal seen in VVS.³⁸ Selective serotonin reuptake inhibitors (SSRIs) block the reabsorption of serotonin into neurons, and is thus postulated to prevent or lessen the sympathoihibitory effects of serotonin in the central nervous system (Figure 5).³⁹ There are very limited studies studying the effect of selective serotonin reuptake inhibitors.¹⁴

Di Girolamo et. al. performed a randomized, double-blind placebo-controlled trial on 68 patients (mean age 45 years old) with recurrent syncope (with a mean of over 7 yearly syncopal episodes) using paroxetine 20mg orally daily versus placebo. Spontaneous syncope recurrence was significantly lower in the paroxetine group (17.6%) compared to the placebo group (52.9%) during two-year follow-up.⁴⁰ Unfortunately, other studies have failed to demonstrate similar results.^41,42

ESC does not have recommendations on the use of SSRI in VVS.¹⁵ The ACC/AHA/HRS guidelines have a weak (Class IIb) recommendation for considering them in VVS patients.¹⁷

Norepinephrine Reuptake Transport Inhibitors

The norepinephrine transporter (NET) is in adrenergic neurons, where it functions to clear away NE released in sympathetic synapses.³⁹NET inhibition results in increased sympathetic tone.⁴³

The POST VI trial was a proof of principle randomized controlled trial that tested the effects of the NET inhibitor, amoxetine (dose of 40mg daily), on tilt-induced syncope. It showed that amoxetine impressively reduced HUTT-induced syncope by about half (35% vs 70%; p = 0.003). Amoxetine significantly decreased reflex bradycardia towards the end of the vasovagal reflex, thereby preventing final falls in the cardiac output and BP.³⁹ The Study of Atomoxetine in the Prevention of Vasovagal Syncope (POST VII trial, ClinicalTrials.gov Identifier: NCT05159687) is an ongoing RCT that will compare the effects of atomoxetine against placebo in patients with recurrent VVS.

There are no guideline recommendations on their use and further larger randomized placebo-controlled trials on their effects on VVS are required.

Interventional Treatment for Vasovagal Syncope

Multiple studies have shown the potential benefit for pacemaker implantation, and more recently, cardioneuroablation for cardioinhibitory VVS. Both also mechanistically aim to address the abnormal and/or exaggerated vagal response in VVS (Figure 5).

Permanent Pacemaker for cardioinhibitory Vasovagal Syncope

Cardiac pacing is the only therapy of proven efficacy in predominantly cardioinhibitory VVS (VASIS Type IIa and Type IIb).⁴⁴ Several previous studies have supported the efficacy of a dual-chamber pacemaker (DDD) compared with unpaced controls. However, further well-designed randomized trials, in which all patients received a pacemaker and were randomly assigned to pacing “on” versus pacing “off’, were unable to demonstrate a clinically significant reduction of syncope, suggesting a large placebo effect from pacemaker implantation.⁴⁴

The SPAIN Study is the first randomized, double-blind trial that showed that DDD- closed loop simulation (CLS) pacing was superior to sham dual chamber pacing “off’ (DDI mode only at 30 beats per minute) in reducing syncope recurrence in patients with predominantly cardioinhibitory syncope.⁴⁵ DDD-CLS pacing is a type of physiologic pacing algorithm with a contractility sensor, known as CLS. In VVS, it has been suggested that increased cardiac contractility (which leads to ventricular mechanoreceptor activation that triggers the vasovagal reflex) occurs right before syncope. The CLS algorithm utilizes its intracardiac impedance sensor to estimate cardiac contractility, with the aim to increase the pacing rate prior to the onset of VVS. The SPAIN Study enrolled 46 Canadian and Spanish patients ≥ 40 years of age with a high syncope burden (≥ 5 syncopal episodes with ≥ 2 episodes in the prior year) and cardioinhibitory HUTT results. It showed superiority over sham dual chamber pacing, reducing the syncope burden by over 50% over 70% of patients with recurrent VVS, with an impressive 37% absolute risk reduction in time to first recurrence of syncope in 1 year, with a number needed to treat of 2.7 to prevent a syncope relapse.⁴⁵

The BIOSync CLS trial, a recent, placebo-controlled RCT in patients aged 40 or older with at least 2 episodes of VVS and tilt-induced syncope with an asystolic pause of >3 seconds similarly showed that dual chamber CLS algorithm markedly reduced syncope recurrence compared to sham control dual chamber pacemaker with no active pacing.⁴⁶

Evidence from the above studies have prompted ESC to find sufficient evidence to upgrade its dual-chamber pacing level of recommendation from Class IIA to Class 1A for patients aged >40 years old with severe recurrent syncope with spontaneous documented symptomatic asystolic pauses >3 seconds or asystolic syncope during tilt testing.¹⁵ Further formal parallel trials comparing DDD versus DDD-CLS pacing are needed to determine the best selection of pacing mode in these patients.

Cardioneuroablation for cardioinhibitory Vasovagal Syncope

Pachon et al performed the first cardioneuroablation for VVS in 2005.³ The premise for cardioneuroablation (CNA) in VVS is to lower the vagal tone by primarily ablating (through radiofrequency ablation) the intrinsic cardiac ganglia and vagal fibers within the GPs in epicardial fat pads.⁵ Although intrinsic cardiac ganglia contain both sympathetic and parasympathetic fibers, as noted in the first part of this review, parasympathetic pre-ganglionic fibers pass through and synapse with the intrinsic cardiac ganglia within the GPs located in the epicardial fat pads before going further into the heart.^3,5,7 In contrast, majority of the postganglionic sympathetic fibers pass directly to the heart without going through the GP.³ Thus, it is assumed that through ablation around the region of the ganglionated plexi, there will be a predominantly parasympathetic denervation of the heart.^2,3

Piotrowski et al conducted the first RCT documenting the efficacy of cardioneuroablation versus optimal nonpharmacological therapy in patients with cardioinhibitory VVS.⁴⁷ It is a prospective, open trial that enrolled 48 young (mean age 38 years) and otherwise healthy patients with refractory (average of 10 syncopal episodes) cardioinhibitory (Type IIa or Type IIb based on HUTT) VVS. ³¹ CNA was performed using radiofrequency ablation of the GP from the left and right atria. At 2-year follow-up, the primary endpoint of first syncope recurrence occurred in 8% of the CNA group versus 54% in the control group (p = 0.0004). Holter electrocardiography also showed significantly faster sinus rhythm rates and increased heart rate variability from baseline in the CNA group, consistent with parasympathetic withdrawal.⁴⁷ It should be noted that this RCT did not have a sham-controlled group to account for the potential placebo effect experienced from the procedure itself. In addition, non-pharmacological therapy was not standardized in the non-pharmacologic group, with rare (only 5 of 48 patients) use of pharmacologic therapy.⁴⁷

So far, there are no guideline recommendations on the use of CNA in cardioinhibitory VVS. In addition, there is no consensus yet on the standardized approach to performing cardioneuroablation, or on patient selection criteria. Further RCTs comparing CNA with sham-controlled patients and standardized optimal nonpharmacological or pharmacological therapy are still warranted to assess the effects of CNA in cardioinhibitory VVS.

Clinical Care Points

• Vasovagal syncope (VVS) is a common, non-life-threatening cause of syncope.

• Knowledge of the autonomic nervous system of the heart is essential in understanding the mechanism of VVS.

• The baroreceptor reflex plays an integral part in monitoring and maintaining normal blood pressure.

• In vasovagal syncope, the baroreceptor reflex is counteracted or overridden, leading to paradoxical hypotension and/or bradycardia than then result in syncope.

• The cornerstone for VVS treatment is non-pharmacological treatment which aims to prevent or mitigate the effects of the vasovagal reflex in VVS. All patients with vasovagal syncope should be educated about these non-pharmacological VVS therapies as they are proven to be effective in most cases of vasovagal syncope.

• Midodrine has been shown to be an effective pharmacological therapy in patients with recurrent, refractory vasovagal syncope. Other pharmacological therapies for VVS can be considered in cases of refractory symptoms despite optimal non-pharmacological therapy, with careful attention to their potential side effects and contraindications.

• Dual chamber pacemaker (DDD-CLS or DDD) has been demonstrated to be effective in cardioinhibitory VVS patients over 40 years old with recurrent syncope. Further trials are needed to determine the optimal pacing mode for these patients.

• Cardioneuroablation is a promising emerging therapy for refractory cardioinhibitory VVS. Further sham-controlled, randomized studies are warranted to assess its effectiveness in cardioinhibitory VVS.

Conclusions

Vasovagal syncope is a common, non-life-threatening cause of syncope due to an abnormal neurally-mediated response. Knowledge of the autonomic nervous system of the heart helps us better understand the mechanism of VVS. This understanding will help physicians educate patients about the triggers and treatment options for VVS. Non-pharmacological therapy remains the cornerstone of treatment for VVS, with pharmacological and procedural therapy for certain cases. Regardless of the type of therapy, they all aim to address or prevent the abnormal neural response seen in VVS patients.

Key Points:

1. Vasovagal syncope (VVS) is a complex condition influenced by the intricate interplay within the autonomic nervous system (ANS).

2. Autonomic dysfunction plays a pivotal role in the pathophysiology of VVS, affecting the balance between sympathetic and parasympathetic branches of the ANS.

3. This review article offers valuable insights into the underlying mechanisms of VVS, shedding light on the intricate relationship between the ANS and this enigmatic condition.

4. Beyond its mechanistic exploration, the article also delves into established and emerging research on the management of vasovagal syncope.

5. Readers seeking a comprehensive understanding of VVS and its connection to the autonomic nervous system will find this review to be a valuable resource addressing both clinical and mechanistic aspects.